カテゴリー: News & Events

An amide-to-chloroalkene substitution improves the peptide permeability

Sayuri Takeo, Chihiro Iio, Ai Sakakibara, Mio Takeda, Yuki Yamazaki, Kohei Sato, Nobuyuki Mase, Mizuki Watanabe, Tetsuo Narumi

Chem Rxiv, 2024. DOI: 10.26434/chemrxiv-2024-l36zv

This study highlights the novel application of Chloroalkene Dipeptide Isosteres (CADIs) in enhancing peptide membrane permeability. Replacing the peptide bond with CADIs in model dipeptides significantly improved passive permeability. This enhancement is attributed to the increased lipophilicity provided by the CADI substitution, as confirmed by AlogP calculations and HPLC retention times. Molecular dynamics simulations further indicated that CADI substitution reduces water interaction, potentially lowering hydration energy. Our findings demonstrate that CADI incorporation can effectively improve the permeability of peptides, offering a valuable approach for developing bioactive peptidomimetics with enhanced pharmacological properties including permeability and hydrolytic stability.

Identification of Peptide-Based Hepatitis B Virus Capsid Inhibitors Based on the Viral Core Protein

Kazutoshi Kawahara, Junko Fujimoto, Sayuri Takeo, Kohei Sato, Kenji Nakashima, Nobuyuki Mase, Masaru Yokoyama, Tetsuro Suzuki, Tetsuo Narumi 

ChemRxiv, 2024. DOI: https://doi.org/10.26434/chemrxiv-2024-p5jb1

In this study, we have identified two novel peptides, 19Ac (comprising residues 91-105) and 20Ac (encompassing residues 96-110), from a systematically designed peptide library based on the Hepatitis B virus (HBV) core protein, that inhibit the assembly of HBV capsid. Peptide 20Ac exhibited about twofold the inhibitory potency of 19Ac and proved effective against both standard and morphothiadin (GLS4)-resistant HBV strains. Molecular dynamics simulations revealed that despite their overlapping sequence, 19Ac and 20Ac bonded to different regions of the core protein, thereby inhibiting capsid assembly through distinct mechanisms. These peptides could serve as valuable seed compounds for the further development of HBV capsid inhibitors, including GLS4-resistant strains.

Development of Novel Amino Acids Containing N-mercaptophenetyl (MPE)-type Auxiliary and Orthogonal Protecting Groups for Sequential Ligation of Multiple Peptides

Yoshinori Taguchi, Kohei Watanabe, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

ChemistrySelect 2024, 9, e202402339.

Novel amino acids containing N-mercaptophenethyl-type auxiliary and orthogonal protecting groups (tert-butyloxycarbonyl (Boc), 1,3-thiazolidine-4-carbonyl (Thz), and allyloxycarbonyl (Alloc)) were developed and applied to sequential ligation of multiple peptides in a one-pot fashion. The combination of these acids enables the synthesis of a branched peptide featuring a lysine side chain.